Chronic inflammation has long been associated with increased risk of cancer development. For example, patients with ulcerative colitis have an increased risk of developing colorectal cancer. Tumor-associated macrophages (TAMs) have been implicated in connecting the innate immune system, chronic inflammation and tumorigenesis, as the appearance of macrophages in tumors corelates with poor patient prognosis, increased lymph node involvement, and distant metastases. TAMs are a heterogeneous myeloid population that infiltrates predominantly hypoxic regions within solid tumors, where they secrete growth factors and cytokines that stimulate angiogenesis and facilitate invasion and/or metastasis. Several studies have implicated the oxygen-sensitive hypoxia inducible factor (HIF) transcriptional regulators in controlling TAM response to hypoxia. In particular, elevated expression of HIF-2 in TAMs corresponds with poor prognosis and high-grade tumors in a variety of human cancers. Specific deletion of HIF-2 in macrophages suppresses primary tumor burden in a mouse model of colitis-associated colon carcinoma. HIF-2 deficient macrophages express reduced levels of proteins mediating angiogenesis and invasion in vitro. The central hypothesis of this proposal is that HIF-2 is required for hypoxic TAMs to express critical factors that promote tumor angiogenesis and metastasis, and thereby drive tumor progression. Based on this hypothesis, I will pursue two specific aims. Specific Aim 1: To determine the role of myeloid-specific HIF-2 signaling in the secretion of pro-angiogenic factors in an inflammatory murine model of colitis-associated colon cancer. Specific Aim 2: To determine how loss of HIF-2 in macrophages supreses tumor progresion and metastasis in a murine model of colon cancer. To complete these studies I will combine in vitro and in vivo methods of cell biology, biochemistry, immunohistochemistry, live imaging, genetics, and animal modeling. The objective of this proposal is to elucidate the underlying mechanisms of HIF-2 expression in the innate immune system, improve our understanding of how hypoxia regulates inflammation-associated cancer, and the unique role tumor microenvironment plays in fueling tumor progression and thereby identify novel therapeutic targets which will facilitate new treatments for colon cancer.